Protein mutation targeted as source of heart problem
By Ruth SoRelle, M.P.H.
A tiny mutation affecting the structure of a microscopic cell explains the inherited heart problem called long QT syndrome in about one-fourth of people with the disorder, said researchers at Baylor College of Medicine, the Texas Heart Institute and Texas Children's Hospital in a report in the journal Circulation: Arrhythmia and Electrophysiology.
Finding clears up mystery
Until this work, scientists were at a loss to explain why these people had the disease, said Matteo Vatta, Ph.D., assistant professor of pediatric-cardiology at BCM. A mutation in a cytoskeletal protein called alpha-1-synotrophin, one of the molecules that helps heart cells maintain their shape, changes the functioning of a tiny pore called a sodium ion channel, resulting in long QT syndrome in at least a portion of these patients, said Vatta, who is also associate director of pediatric cardiac research. Vatta is senior author of the report.
Ion channel defects alone blamed before
Until now, defects in genes for particular ion channels have been blamed for inherited long QT syndrome, said Vatta. However, experts could identify no defects in about 25 percent of people with the problem.
Ions are charged chemicals such as sodium or potassium that flow in and out of pores called channels in the cell membranes. The channels open and close in a specific sequence, letting the chemicals in and out of the cells in a manner that prompts them to beat in synchrony. When the cells can beat in unison, the heart pumps blood. If the ion channels are defective, it affects the beating of the cells and the heart – often with devastating effects. Untreated long QT syndrome can cause the heart to stop suddenly.
"The mutation in this kind of protein called alpha-1-syntrophin is the first associated with long QT syndrome," said Vatta. Previously, he and colleagues had identified a link between long QT syndrome and a defect in caveolin-3, a scaffolding protein.
Connection between structure, electrical activity
"I am interested in the connection between the structural and the electrical part of the heart," said Vatta, whose lab is based in the Feigin Center of Texas Children's. "It could have everything to do with susceptibility to arrhythmias (heart rhythm disruptions) in patients with heart disease. First, we had to prove that the structural part of the heart could be involved in electrical problems."
The caveolin-3 finding led to studies of syntrophin, a protein connected to dystrophin, which when mutated causes Duchenne and Becker muscular dystrophy as well as the X-linked form of cardiomyopathy. As people with Duchenne and Becker muscle-wasting disease age, they develop cardiomyopathy, a weakening of the heart muscle, with heart rhythm disruptions called arrhythmias. This leads to heart failure and an increased risk of sudden cardiac death (sudden heart stoppage) caused by the arrhythmias.
Dystrophin binds syntrophin
"Syntrophin is the bridge that connects dystrophin to the sodium channel," said Vatta. Dystrophin is critical in the binding of syntrophin to the sodium channel, he said. A mutation in syntrophin disrupts the proper functioning of the sodium channel.
That leads to an electrical problem that disrupts the normal beating of the heart, he said. The finding is proof of the concept that patients with mutations in the structural part of the heart muscle cells also have a problem with how the electrical system of the heart works, leading to dysrhythmias.
Interactions important
"Once you screen all the ion channels and do not find changes that can lead to a pathological effect such as long QT syndrome, then you have to think about all the proteins that interact with the ion channels," Vatta said.
Others who took part in this study include Geru Wu, Tomohiko Ai, Yutao Xi, Shahrzad Abbasi, Kaveh Samani and Jie Cheng, all of the Texas Heart Institute/St. Luke's Episcopal Hospital in Houston; Jeffrey J. Kim, Bhagyalaxmi Mohapatra, Zhaohui Li, Enkhsaikhan Purevjav and Jeffrey A. Towbin, all of BCM and Texas Children's; Michael J. Ackerman of the Mayo Clinic in Rochester, Minnesota, and Ming Qi and Arthur J. Moss of the University of Rochester Medical Center in New York.
Support for this work came from the National Heart, Lung, and Blood Institute and the National Institute of Child and Health Development, the Roderick D. MacDonald General Research Fund, the Cardiovascular Initiative Grant from the St. Luke's Episcopal Hospital/Texas Heart Institute and the Texas Children's Foundation.
An abstract of this report is available.
